Studies of the cellular and molecular mechanisms underlying the sequential cleavage of the amyloid precursor protein (APP) to p-amyloid (Ap) by p- and y-secretases have afforded great nsight into the etiology of Alzheimer's Disease (AD). Understanding the mechanisms that regulate Ap generation may enable the development of pharmacologically active compounds that target Ap formation. Our work supported by this Program Project Grant has identified the serine/threonine protein kinase CK1 as an important regulator of APP processing. CK1 has been implicated in everal important neuronal processes, including dopamine signaling in striatum, circadian rhythm, brain receptor signaling, and AD. Notably, CK15 mRNA is up-regulated in brain tissue from AD patients, and CK1 may phosphorylate and regulate a number of proteins that likely play an important role in AD, for example, p- and y-secretases. CK1 has also been implicated in tau hyper- phosphorylation and aggregation, another hallmark of AD pathogenesis. The long-term objective of Project 3 is to study the molecular mechanisms underlying CK1-dependent increases in Ap production. In Aim I, we will investigate the cellular process(es) responsible for the effects of CK1 and in Aim II we will identify the protein targets (eg BACE, presenilin) that mediate the effects of CK1. Little is known about regulation of CK1, but it is known from our studies to be regulated in neurons by metabotropic glutamate receptors. In Aim III we will investigate the molecular basis for the regulation of CK1 by neurotransmitters such as glutamate, and in Aim IV we will investigate the role of several new proteins that we have found to interact with CK1. In these studies, we will collaborate with other Projects in the Program Project Grant in our studies of the role of CK1 in APP processing (Project 2), and synaptic structure and function (Project 1). We will also utilize key reagents and cell-based assay systems generated by Core B. These studies will lead to greater knowledge of mechanisms involved in the production of Ap in the brains of AD patients and will hopefully identify novel proteins that can be targeted by therapeutic agents.